Peroxiredoxin (Prx) is a scavenger of hydrogen peroxide and alkyl hydroperoxides in living organisms (Chae, H. Z. et al., Proc. Nat. Acad. Sci. 91: 7017-7021, 1994). There are six distinct mammalian Prx isozymes, types I to VI, that are detected in a wide range of tissues (Rhee, S G et al., IUBMB Life, 52:35˜41, 2001). These have been found to have potent antioxidant activities in vivo. All of the known mammalian Prxs, except for type VI, utilize thioredoxin as an electron donor, and thus were formerly known as thioredoxin peroxidases.
In addition to their antioxidant activity, Prxs have been implicated in various cellular functions including cell proliferation and differentiation, enhancement of natural killer cell activity, protection of radical-sensitive proteins, heme metabolism, and intracellular signaling (Nemoto Y, et al., Gene, 91:261˜265, 1990; Prosperi M T, et al., Genomics, 19:236˜241,1994; Tsuji K, et al., Biochem J. 307:377˜381, 1995; Shau H, et al., Immunogenetics, 40:129˜134,1994; Watabe S, et al., Biochem Biophys Res Commun. 213:1010˜1016, 1995; Iwahara S, et al., Biochemistry, 34:13398˜13406, 1995; Wen S T, et al., Genes Dev. 11:2456˜2467, 1997). The biochemical characteristics revealed from cultured animal cell studies show that Prx may be one of those that play important roles in maintaining cellular redox potential.
Of these antioxidant proteins, 2-cys peroxiredoxin type II (Prx II) is a cellular peroxidase that eliminates endogenous H2O2 produced in response to growth factors including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF).
It is known that Prx II is located in abundance in the cytoplasm of cells, binds to integral membrane proteins or cell membranes via its C-terminal region, and has a high affinity for H2O2 (Km for H2O2<10 μm).
Also, Prx II is found to be highly expressed in erythrocytes and to play a protective role against reactive oxygen species (ROS)-mediated damage in these cells, and is induced at the early stages of erythroid differentiation prior to hemoglobin accumulation (Rabilloud T, et al., Biochem J. 312:699-705, 1995).
Platelet-derived growth factor (PDGF) is a potent mitogenic and migratory factor that regulates the tyrosine phosphorylation of a variety of signaling proteins through the generation of endogenous H2O2. Particularly, PDGF stimulates the proliferation and migration of smooth muscle cells during vascular remodeling. In this regard, Prx II serves as an important regulator for the PDGF-mediated generation of H2O2, but its precise function in signal transduction has yet to be proven.
Based on the observation that Prx II−/− mice have hemolytic anemia, Lee T H et al., suggested that Prx II plays a major role in protecting RBCs from oxidative stress in mice (Lee T H et al., Blood, 101(12):pp 5033-5038, 2003). U.S. Pat. Publication No. 2002/0168353 discloses a composition for the treatment of HIV infection, comprising purified type I Peroxiredoxin and type II Peroxiredoxin.
Restenosis, or renarrowing, is said to recur in as many as 50% of stenosis cases or more, as determined by coronary angiography after coronary angioplasty. Being a major obstacle to the successful treatment of cardiovascular diseases, restenosis occurs in about 30% of patients who receive coronary angioplasty (balloon dilatation and stent insertion).
Restenosis, although the precise mechanism thereof. must be further revealed, is known to be attributed to the fact that growth factors and cytokines are locally secreted due to vascular endothelial cell injury during angioplasty or balloon dilatation and induce smooth muscle cell proliferation and migration through autocrine and paracrine mechanisms, leading to the narrowing of artery lumens. Hence, smooth muscle cell proliferation has recently been recognized as a clinical problem that is important in the effectiveness of coronary angioplasty (Bauters C, Isner J M, Prog Cardiovasc Dis. 40(2):107-116, 1997, U.S. Pat. Nos. 6,780,406 and 6,740,678).
Extensive studies have been conducted to reduce or prevent restenosis. Particularly, many attempts have been made to regulate smooth muscle cell proliferation, using angiotensin converting enzyme (ACE) inhibitors, antisense RNAs for cell cycle regulatory proteins, and thymidine kinase genes (Rakugi et al, J. Clin. Invest., 93:339-346, 1994; Simons et al., Nature, 359:67-70, 1992; U.S. Pat. No. 6,780,406).
Leading to the present invention, the intensive and thorough study on intracellular functions of Prx II, conducted by the present inventors, resulted in the finding that Prx II is involved in vascular muscle cell migration, thereby being used in preventing or reducing vascular restenosis.